事與愿違的大型臨床試驗結(jié)果告訴了我們什麼

What We have Learned from the Failure of Large Clinical Trials? 事 與 愿 違 的 大 型 臨 床 試 驗 結(jié) 果 告 訴 了 我 們什 麼 ? HUI Rutai 惠 汝 太 Beijing FuWai Hospital, China 北 京 阜 外 醫(yī) 院 高 血 壓 中 心 主 任 prioritizes target levels of some risk factors: plasma sugar blood presure cholestrol Womens Health Initiative RCT revealed that hormone-replacement therapy, which reduces LDL cholesterol levels, increased the risk of cardiovascular disease. (Anderson et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701-1712) ENHANCE ENHANCE: Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia Kastelein et al: NEJM 2008,358:1431-1443; Correction: NEJM 2008,358:1977 ENHANCE showed that ezetimibe did not reduce the progression of arteriosclerosis when combined with simvastatin, as compared with simvastatin alone, even though the combination did result in a greater reduction of LDL cholesterol. Kastelein et al: NEJM 2008,358:1431-1443; Correction: NEJM 2008,358:1977 Post-trial Study UKPDS (UK Protective Diabetes Study) Type-2 DM: low plasma glucose, Reduction in microvascular complications. Whether the therapy can reduce macrovascular complications? 降糖治療試驗停止后，持續(xù)隨訪10年的結(jié)果 Holman et al NEJM 2008:359: Any DM-related Endpoints： sudden death， death from hyperglycemia, hypoglycemia, fatal, non-fatal MI, angina, heart failure, fatal, non-fatal Stroke, renal failure, amputation, vitreous hemorrhage, retinal photo-coagulation, blindness in one eye, hyperglycemia, Hypoglycemia.Microvascular disease: vitreous (玻璃體)hemorrhage, retinal photo-Coagulation(視網(wǎng)膜光凝術(shù) ), renal failure, Follow-up 10 years Sulfonylurea-Insulin MetoforminAny DM-related Endpoints 9% (P=0.04) 21% (P=0.01)Microvas Dis 24%(P=0.001)MI 15% (P=0.01) 33%(P=0.005)Death fromAny cause 13%(P=0.007) 27% (P=0.002)與傳統(tǒng)限制飲食治療比較，藥物強化治療 Holman et al NEJM 2008:359: ADVANCE The ADVANCE：action in diabetes and vascular disease - preterax and diamicron MR controlled evaluation. Diabetologia 2001;44:1118-1120 Collaborative Group NEJM 2008, 358:2560-2572 ADVANCE 11,140 patients with type 2 diabetes ; Grouped: 1. standard glucose control 2. intensive glucose control: gliclazide (格列齊特, 達美康 modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points: 1. composites of major macrovascular events: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 2. major microvasc events: new or worsening nephropathy or retinopathy ADVANCE After a median of 5 years of follow-up, Intensive Standard HR 95% CI P Glycated hemoglobin 6.5% 7.3% Combined major macrovascular P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). Meta-analysis： Rosiglitazone （Avandia） Rosiglitazone improves glucose control, but it may also be associated with increased cardiovascular risk. (Nissen et al. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-2471) ONTARGET Ongoing Telmisartan Alone and in Combination with Ramipril(雷米普利 ) Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004;148:52-61. ACEI reduce mortality and morbidity from cardiovascular causes, but the role of ARBs in such patients is unknown. The aim of the study was to compare the ACEI ramipril, ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes. The ONTARGET Investigators, NEJM 358:1547-1559 ONTARGETGroups: 1.ramipril 10 mg qd 2.telmisartan 80 mg qd 3. Combination of the two drugsPrimary composite outcome: 1.death from cardiovascular causes, myocardial infarction, stroke, 2.hospitalization for heart failure. Results A median follow-up of 56 months, vs. ramipril telmisartan combination 1. Mean blood ressure 0.9/0.6 mm Hg 2.4/1.4 mm Hg greater greater 2. outcome ramipril: 1412 (16.5%), telmisartan: 1423 (16.7%; RR 1.01; 95%CI, 0.94-1.09 vs. ramipril). combination: 1386 (16.3%; RR 0.99; 95% CI, 0.92-1.07 vs. ramipril); 3.side effects: telmisartan: cough (1.1% vs. 4.2%, P0.001 vs. ramipril ) angioedema (0.1% vs. 0.3%, P=0.01 vs. ramipril ) hypotensive symptoms (2.6% vs. 1.7%, P0.001 vs. ramipril ); syncope: the same in the two groups (0.2% vs. ramipril ). combination : hypotensive symptoms (4.8% vs. 1.7%, P0.001 vs. ramipril ), syncope (0.3% vs. 0.2%, P=0.03 vs. ramipril ), renal dysfunction (13.5% vs. 10.2%, P0.001 vs. ramipril ). KaplanMeier Curves for the Primary Outcome in the Three Study Groups. Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. Adding an angiotensin-receptor blocker to an angiotensin-convertingenzyme inhibitor may produce a greater reduction in blood pressure, but it may not reduce cardiovascular risk and it increases the risk of other adverse events. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559. ONTARGET ACCORD ACCORD (Action to Control Cardiovascular Risk in Diabetes) NEJM 2008，358:2545-2559 Strategy：the use of multiple medications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus. ACCORD Methods In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive targeting glycated hemoglobin Intensive therapy：below 6.0%； Standard therapy： 7.0 to 7.9%. Primary outcome： composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. ACCORDAt 1 year Results Intensive Standard HR，95% CI P Stable median Glycated hemoglobin 6.4% 7.5% Primary outcome（n） 352 371 0.90 0.78-1.04; 0.16 Death （n） 257 203 1.22; 1.01-1.46 0.04 Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P0.001). ACCORD As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes ADVANCE ADVANCE (Action in Diabetes and Vascular Disease: Preterax (復方:配德利錠: PERINDOPRIL培哚普利 1.669mg +吲哚帕胺INDAPAMIDE 0.625mg ) and Diamicron Modified Release Controlled Evaluation. Strategy：the use of multiple medications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus. ADVANCE The ADVANCE studys findings indicate that its strategy may reduce the risk of worsening renal function at the cost of an excess risk of hypoglycemic events. torcetrapib ：a promising agent that lowered LDL cholesterol levels and raised high-density lipoprotein (HDL) cholesterol levels. the tendency of torcetrapib to cause blood pressure to rise and potassium levels to fall attracted much more attention after December 2006 than it had previously. ILLUMINATE Trial (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) Patients receiving torcetrapib plus atorvastatin had a higher mortality rate than those receiving atorvastatin alone despite 72% increases in HDL levels and 25% decreases in LDL levels. （Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-1316） on December 2, 2006, the day Pfizer stopped ILLUMINATE trial and all other trials involving torcetrapib. Some strategies are known to improve patient outcomes, whereas others are known to affect only risk-factor levels or other intermediate outcomes. We are now beginning to appreciate that a strategys effect on a risk factor may not predict its effect on patient outcomes. Lifestyle interventions may have few risks, but we cannot assume the same for drugs and drug-related risks are not always known or appreciated. considerations of the risks of disease adverse consequences posed by the intervention. an intervention designed to protect against that outcome is unlikely to provide substantial benefit so if the intervention carries even a small risk, this risk can offset or even outweigh the benefit. In sicker patients and those with more complex conditions, certain interventions (such as maintenance of tight glucose control) may be more likely to produce adverse effects than they would in healthier patients, either directly or through their effect on adherence. Focus on patient outcomes, improvement, not just intermediate outcomes, not just on surrogate end points. Individualized Medicine 3P Medicine：personalized predictive preventive “Between the healthcare we have and the care we could have lies not just a gap, but a chasm(大峽谷）.” “The lag between the discovery of more efficacious forms of treatment and their incorporation into routine patient care is unnecessarily long, in the range of about 15-20 years.”Major Challenge: Applying What We Know Study design based on Pharmacogenomics Epigenetics/epigenomics Telomere: short or longer 在 人 群 的 遺 傳 素 質(zhì) 是 相 對 穩(wěn) 定 的 情 況 下 ，我 國 疾 病 譜 和 發(fā) 病 率 發(fā) 生 巨 大 改 變 。 這 種變 化 表 明 環(huán) 境 對 疾 病 有 著 巨 大 的 影 響 。 對 結(jié) 腸 癌 、 腦 中 風 、 冠 心 病 和 II型 糖 尿 病等 多 種 復 雜 性 疾 病 的 研 究 發(fā) 現(xiàn) ， 至 少 70的 患 者 受 不 良 的 “ 環(huán) 境 因 素 ” 影 響 ， 如 偏食 、 超 重 、 不 運 動 和 抽 煙 。 而 且 ， 如 果 改變 不 良 生 活 習 慣 ， 可 大 大 地 降 低 這 些 疾 病 。 表 觀 遺 傳 學 定 義 ： “ 在 基 因 組 序 列 不 變 的 情 況 下 ， 可 以決 定 基 因 表 達 與 否 并 可 穩(wěn) 定 遺 傳 下 去 的 調(diào) 控 密 碼 ” 。 表 遺 傳 學 內(nèi) 容 包 括 ： DNA甲 基 化 、 基 因 組 印 記 、 染 色 質(zhì) 組 蛋 白 修 飾 、 隔 離 蛋 白 非 編 碼 RNA (包 括 microRNA) 等 DNA序 列 以 外 的 各 種 調(diào) 控 方 式 ， 任 何 一 方 面 的 異 常 都將 影 響 染 色 質(zhì) 結(jié) 構(gòu) 和 基 因 表 達 ， 導 致 復 雜 綜 合 征 、 多 因素 疾 病 。 環(huán) 境 因 素 的 影 響 短 期 內(nèi) 或 許 難 以 造 成 基 因 序 列 的 改變 ， 但 卻 可 以 改 變 表 觀 遺 傳 密 碼 ， 并 將 這 種 “ 烙 印 ” 傳遞 給 下 一 代 。 科 技 部 中 德 分 子 醫(yī) 學 研 究 室 暨 教 育 部 基 因 與 臨 床 重 點 室科 技 部 /國 家 外 專 局 國 家 級 國 際 合 作 研 究 中 心